RS50114B - NEW POLYMORPHIC FORM 5- / 4- / 2- (N-METHYL-N- (2-PYRIDYL) AMINO / ETHOXY / BENZYL / THIAZOLIDINE-2,4-DION, MALEIC ACID SALTS - Google Patents

Abstract

Polymorphic form of 5- [4- [2- (N-methyl-N- (2-pyridyl) amino] ethoxy] benzyl] thiazolidine-2,4-dione, salt of meleic acid ("Polymorph"), characterized in that: ) gives an infrared spectrum with peaks at 1360, 1326, 1241, 714 and 669 cm-1, and / or (ii) gives a Raman spectrum with peaks at 1581, 768, 670, 271 and 226 cm-1, and / or (iii) provides a solid state nuclear magnetic resonance spectrum with peaks at chemical displacements as given in Table I, and / or (iv) provides an X-ray powder diffraction pattern (XRPD) with peaks as given in Table II. requires.

Description

This invention relates to a new polymorphic form of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione salt of maleic acid, as well as to the procedure for obtaining this pharmaceutical product and to the use of this pharmaceutical product in medicine.

International Patent Application, Publication Number VVO94/05659 describes some thiazolidinedione derivatives having hypoglycemic and hypolipidemic effects, including 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thioazolidine-2,4-dione maleic acid salt (herein also referred to as "Compound (I)").

International Patent Applications, Publication Numbers W099/31 093, VV099/31 094 and VV099/31 095, each describe different hydrates of Compound (I).

Compound (I) has now been found to exist in a new polymorphic form which is particularly suitable for mass production and handling. The new shape can be obtained by an efficient, economical and reproducible process, which is particularly suitable for large-scale production.

The new polymorphic form (abbreviated "Polymorph") also has useful pharmaceutical properties, and has been shown to be particularly useful for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and some of its complications.

Accordingly, the present invention provides a polymorphic form of a salt of maleic acid and 5-[^-(N-Methyl-N^-pyridiOaminoethoxy]benzyl]thiadiazolidine^^-dione, which is characterized by: (i) an infrared spectrum containing peaks at 1360, 1326, 1241, 714 and 669 cm"<1>; and/or (ii) a Raman spectrum containing peaks at 1581, 768, 670, 271 and 226 cm"<1>; and/or (iii) a solid phase nuclear magnetic resonance spectrum, containing peaks at the chemical shifts given in Table I; and/or (iv) an X-ray powder diffraction (XRPD) spectrum containing peaks that are essential

given in Table II.

In a preferred embodiment, this polymorph provides an infrared spectrum substantially conforming to Figure I.

In a preferred embodiment, this Polymorph provides a Raman spectrum substantially in agreement with Figure II.

In a preferred embodiment, this Polymorph provides a solid state nuclear magnetic resonance spectrum substantially in agreement with Figure III.

In a preferred embodiment, this Polymorph provides an X-ray Powder Diffraction (XRPD) spectrum substantially in agreement with Figure IV.

This invention encompasses the Polymorph isolated in pure form or when mixed with other materials, for example with known forms of Compound I, or with any other material.

Thus, in one aspect, the Polymorph is provided in isolated form.

In the following aspect, Polymorph is provided in its pure form.

In a further aspect, Polymorph is provided in crystalline form.

The present invention also provides a process for obtaining Polymorph, characterized in that a thick suspension of Compound (I) in aqueous ethanol containing up to 2.5 m/V % water, preferably an aqueous denatured alcohol containing up to 2.5 m/V % water, for example 2.5 m/V % water, is heated, suitably to a temperature in the range of 35°C to 6C<T>C, such as from 40°C to 50°C, for example at 45°C, for a longer period of time, for example 65 h, after which time Polymorph is isolated from denatured ethanol. Optionally, the reaction mixture can be seeded with Polymorph.

In the following process of this invention, Compound (I) is mixed with denatured ethanol, heated at an elevated temperature, preferably at a temperature in the range of 35°C to 60°C, such as 40°C to 50°C, for example from 45° to 47°C, for a long time, for example 65 h, and' after that time the Polymorph is isolated from the solvent. Optionally, the reaction mixture can be seeded with Polymorph.

In the following procedure, a solution of Compound (I) in denatured ethanol, containing up to 2.5 m/V % water, for example 0.8 to 2.5 m/V % water, is seeded with Polymorph at 55°C and cooled to a temperature in the range of 20°C to 25°C, yielding Polymorph. The polymorph is then isolated from denatured ethanol.

It is convenient to prepare a solution of Compound (I) in denatured ethanol by dissolving Compound (I) in the required amount of denatured ethanol, at an elevated temperature, for example 60°C. In our procedure, this last process is efficiently performed using Compound (I) containing up to 25 wt% hydrate, described in the aforementioned VVO99/31093.

It is convenient to isolate the Polymorph from the reaction solvent, such as denatured ethanol, by filtration and subsequent drying, preferably at an elevated temperature, for example at 45°C.

In a further aspect of the present invention there is also provided a process for obtaining Compound (I) (also referred to for convenience as 'Original Polymorph') from the Polymorph of the present invention, the process comprising firstly preparing a solution of the Polymorph in a mixture (100:1, VA/) of absolute ethanol and methanol, at an elevated temperature, in the range of 60° to 75°C, for example at 68°C, and then allowing this solution to cool to an ambient temperature, for example 20° to 25°C, allowing the Original Polymorph to crystallize.

In a preferred form of said process for the preparation of Original Polymorph, a solution of Polymorph in absolute ethanol/methanol mixture is filtered, and the resulting solution is heated to an elevated temperature, for example 65°C, and the solution is allowed to cool to ambient temperature, for example, 20° to 25°C.

In the aforementioned procedures for obtaining the Original Polymorph, the solution can be seeded with the Original Polymorph, but this is not essential.

Compound (I) is obtained according to known procedures, such as those described in WO94/05659. The description of VVO94/05659 is incorporated herein by reference.

For the avoidance of doubt, the name "Compound (I)" is used herein for the salt form of maleic acid and 57[4-[2-(N-methyl-N(2-pyridyl)amino)ethoxy]benzylthiazolidine-2,24-dione, as described and characterized in International Patent Application, Publication Number VVO94/05659.

When the term "denatured ethanol" is used, it means ethanol containing small amounts of methanol, typically up to 5 vol% methanol, such as from 0.9 vol% to 5 vol% methanol, for example, ethanol containing 4 vol% methanol.

When used herein, the term "prophylaxis of conditions associated with diabetes mellitus" includes the treatment of conditions such as insulin resistance, impaired glucose tolerance, hyperinsulinemia, and gestational diabetes.

Diabetes Mellitus preferably means Type II Diabetes Mellitus.

Conditions associated with diabetes include hyperglycemia and insulin resistance and obesity. The following conditions that are associated with diabetes are hypertension, cardiovascular disease, especially atherosclerosis, some eating disorders, and especially the regulation of appetite and food intake in persons suffering from disorders related to malnutrition, such as anorexia nervosa, and from disorders related to excessive food intake, such as obesity and anorexia bulimia. Additional conditions associated with diabetes include polycystic ovary syndrome and steroid-induced insulin resistance.

Complications of diabetes mellitus-related conditions covered herein are kidney disease, particularly kidney disease associated with the development of Type II diabetes, including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis, and end-stage renal disease.

As mentioned above, the compound of the present invention has useful therapeutic properties: according to the present invention Polymorph is used as an active therapeutic substance.

More particularly, the present invention provides Polymorph for use in the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and some of its complications.

The polymorph can be administered by itself, or preferably, as a pharmaceutical preparation, which also contains a pharmaceutically acceptable carrier. The formulation of Polymorph and its dosages are conventional as described for Compound (I) in International Patent Application, Publication Number VV094/95659 or VV098/66122.

Therefore, the present invention also provides a pharmaceutical preparation consisting of Polymorph and a pharmaceutically acceptable carrier therefor.

Normally, Polymorph is prescribed as a unit dose.

The active compound can be administered by any convenient route, but usually by the oral and parenteral routes. For such use, it is normal for this compound to be used in the form of a pharmaceutical preparation together with a pharmaceutical carrier, diluent and/or additive, although the exact form of the preparation will naturally depend on the method of administration.

The preparations are obtained as a mixture, which is suitable for oral, parenteral or surface administration, and as such can be in the form of tablets, capsules, liquid oral preparations, powders, granules, wafers, lozenges, powders for reconstitution, solutions or suspensions for injections and infusions, suppositories and transdermal patches. Preparations suitable for oral administration are preferred, especially shaped oral preparations, because they are suitable for general use.

Tablets and capsules for oral administration are usually given in unit dose form and contain conventional additives, such as binding agents, fillers, diluents, tableting agents, lubricants, disintegrants, coloring agents, flavorings and wetting agents. Tablets can be coated by methods well known in the art.

Suitable fillers are cellulose, mannitol, lactose and other similar agents. Suitable disintegrants are starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants are, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents are, for example, sodium lauryl sulfate.

Solid oral preparations can be obtained by conventional methods of mixing, filling, tableting and the like. Repeated mixing operations may be used to distribute the active agent within those formulations using large amounts of filler. Of course, these operations are conventional in the state of the art.

Liquid oral preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be prepared as a dry product, for reconstitution with water or other suitable liquid vehicle, prior to use. Such liquid preparations may contain conventional additives, such as suspending agents, for example, sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan monooleate or acacia; non-aqueous liquid carriers (which may include liquid edible oils), for example almond oil, fractionated coconut oil, oil esters such as glycerin, propylene glycol or ethyl alcohol esters; preservatives, for example methyl- or propyl-p-hydroxybenzoate or sorbic acid, and if desired, conventional flavoring or coloring agents.

For parenteral administration, fluid liquid dosage forms are prepared by containing a compound of the present invention and a sterile liquid carrier. The compound, depending on the liquid carrier and concentration, can be either suspended or dissolved. Normally, parenteral solutions are obtained by dissolving the active compound in a liquid carrier and sterilized by filtration, before filling into suitable vials or ampoules and sealing hermetically.

Adjuvants, such as local anesthetics, condoms and buffering agents, may also be dissolved in the liquid carrier. To improve stability, the preparation can be frozen after filling in the vial, and the water removed under vacuum.

Parenteral suspensions are prepared in essentially the same manner, except that the active compound is suspended in a liquid vehicle, rather than dissolved, and is sterilized prior to suspension in the sterile vehicle by exposure to ethylene oxide. It is convenient to add a surfactant or a wetting agent to such a preparation, to facilitate the uniform distribution of the active compound.

In addition, such preparations may contain other active agents, such as anti-hypertensive agents and diuretics.

In addition, Polymorph can be used in combination with other antidiabetic agents, such as insulin secretion promoters, for example sulfonylureas, biguanidines, such as metformin, alpha-glucosidase inhibitors; such as acarbose, beta-agonists and insulin, as well as those described in VV098/57649, VV098/57634, VV098/57635 or VV098/57636. Other antidiabetic agents, their amounts and methods of administration, are described in the above-mentioned publications. The formulation of Polymorph and its dosage in said combinations are usually as described in the above-mentioned publications for Compound (I). As is common practice, these preparations are usually accompanied by written or printed instructions for use in the appropriate medical treatment.

When used herein, the term "pharmaceutically acceptable" includes compounds, preparations and ingredients for both human and veterinary use: for example, the term "pharmaceutically acceptable salt" includes a veterinary acceptable salt.

The present invention further provides a method for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and some of its complications, in human and non-human mammals, comprising administering an effective, non-toxic amount of Polymorph to a human or non-human mammal in need thereof.

It is convenient for the active compound to be prescribed as a pharmaceutical preparation defined earlier, and this represents a special aspect of this invention.

In the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and some of its complications, Polymorph may be administered at doses such as those described above.

Similar dosage regimens are suitable for the treatment and/or prophylaxis of non-human mammals.

In a further aspect of this invention, the use of Polymorph for the manufacture of medicaments for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and some of its complications is provided.

With the above treatments, no adverse toxicological effects were observed for the compounds of the present invention.

The following examples illustrate this invention, but do not limit it in any way.

Example 1:

A thick suspension of Compound (I) (3.0 g, obtained according to VVO94/05659) in denatured ethanol (30.5 ml_, water content 2.5 m/V %) was heated for 65 h at 45 °C. This product was filtered at 45 °C and dried at 50 °C under vacuum to give Polymorph (1.15 g).

Example 2

Compound (I) (2.00 g) was added to a mixture of absolute ethanol (30 mL, water <0.1 m/V %) and methanol (1.2 mL). The resulting suspension is heated to 45-7°C and kept at that temperature for 65 hours. A solid is isolated at 45° C., then dried at 50° C. under vacuum, yielding 0.83 g (41%) of Polymorph.

Example 3

Compound (I) (6.0 g, containing approximately 25 wt% of the hydrate described in VVO88/31093) is heated at 60°C in denatured alcohol (60 mL, water content 0.8 m/V %) until complete dissolution occurs. The resulting solution was cooled to 55°C, seeded with the title compound (0.06 g), then cooled to 20-25°C. The product was filtered, washed with denatured ethanol (10 mL) and dried at 50°C under vacuum to give Polymorph (4.8 g, 80%).

Example 4: Conversion of Polymorph to Compound (I) (Original Polymorph)

The polymorph (4.0 g) was heated to 68°C in a mixture of absolute ethanol (40 mL) and methanol (0.4 mL) until complete dissolution was obtained. The resulting solution is filtered, reheated to 65°C, then cooled to 20-25°C. The product was filtered, washed with absolute ethanol (8 mL) and dried at 50°C under vacuum to give Compound (I) as described in VVO94/05659 (3.32 g, 83%).

Characterization data:

The following data were obtained for the characterization of Polymorph:

A. Water content

Using Karl Fischr's apparatus, a water content of 0.8% by mass was determined.

B.Infrared spectrum

The absorption spectrum in the infrared region for the dispersion of Polymorph in mineral oil was obtained in a Nicolet 710 FT-IR spectrometer, with a resolution of 2 cm"<1>. The data was digitized at intervals of 1 cm"<1.>The resulting spectrum is shown in Figure I. The peak positions are as follows: 2720, 1750, 1703, 1640, 1618, 1610, 1573, 1541, 1529, 1513, 1412, 1360, 1326,1309, 1300, 1265, 1241, 1213,1183, 1162, 1112, 1096, 1080, 1068, 1033, 1014, 989, 972, 933, 902, 866, 843, 832, 812, 774, 741, 734, 729, 669, 660, 636, 613, 605, 577, 558, 540, 527, 515, 508 and 473 cm"1.

C. Raman spectrum

The Raman spectrum of Polymorph was recorded through a glass vial, using a Perkin Elmer 2000R spectrometer, with a resolution of 4 cm"<1>, and is shown in Figure II (the X-axis shows the intensity, and the Y-axis shows the Raman shift in cm"<1>, 1800-200 cm"<1>). Excitation is achieved using a Nd:YAG laser (1064 nm), with a power of 400 mW. The peak positions are as follows: 1749, 1706, 1683, 1611, 1581, 1546, 1511, 1468, 1445, 1435, 1388,1361, 1327,1301, 1269,1250, 1229, 1210, 1179, 1149, 1103, 1056, 1036, 1024, 1005, 989, 920, 843, 827, 800, 782, 768, 744, 722, 670, 637, 605, 560, 541, 512, 473, 429, 408, 397, 347, 322, 298, 271 and 226 cm"<1>.

D. Solid state NMR spectrum

The spectrum of Polymorph at 90.56 MHz for<13>C CP-MAS NMR is shown in Figure III. The chemical shifts are given in Table I. Data were recorded at ambient temperature and a spin frequency of 10 kHz, on a Bruker AMX360 spectrometer, with a cross-polarization of 1.6 ms and a repetition time of 15 s. Chemical shifts are given against the external reference carboxylate signal of the glycine test sample, at 176.4 ppm, relative to tetramethylsilane, and are considered accurate to within ±0.5 ppm. Spades are not marked.

E. X-ray powder diffraction (XRPD) spectrum

The XRPD spectrum for Polymorph is shown in Figure IV, and an overview of the XRP angles and calculated lattice distances characterizing Polymorph is given in Table II.

A PVV1710 X-ray powder diffractometer (Cu X-ray source) was used to generate the powder spectrum, with the following acquisition conditions:

Claims (13)

1. Polymorphic form of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione, salt of maleic acid ("Polymorph"), characterized by: (i) giving an infrared spectrum with peaks at 1360, 1326, 1241, 714 and 669 cm'1; and/or (ii) giving a Raman spectrum with peaks at 1581, 768, 670, 271 and 226 cm"<1>; and/or (i and i) gives a solid state nuclear magnetic resonance spectrum with peaks at chemical shifts as given in Table I; and/or (iv) gives an X-ray powder pattern (XRPD) with peaks as given in Table II. 2. Polymorph according to claim 1, characterized in that it gives the infrared spectrum shown in Figure I. 3. Polymorph according to claim 1 or claim 2, characterized in that it gives the Raman spectrum shown in Figure II. 4. The polymorph according to one of claims 1 to 3, characterized in that it gives the solid state nuclear magnetic resonance spectrum shown in Figure III. 5. Polymorph according to one of claims 1 to 4, characterized in that it gives the X-ray powder pattern (XRPD) shown in Figure IV. 6. Polymorph according to one of claims 1 to 5, characterized in that it is in pure form or mixed with other materials. 7. Polymorph according to claim 5, characterized in that it is in pure form. 8. Polymorph according to one of claims 1 to 7, characterized in that it is in crystalline form. 9. The method for obtaining Polymorph according to claim 1, characterized in that: (a) a suspension of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]-benzyl]thiazolidine-2,4-dione salt of maleic acid (hereinafter "Compound I" or "Original Polymorph) in aqueous ethanol containing up to about 2.5% t/z water, was heated for a long time; after which Polymorph was isolated from of denatured ethanol; or (b) Compound (I) is mixed with denatured ethanol, heated at an elevated temperature, after which the polymorph is regenerated from the solvent; or (c) Compound (I) in denatured alcohol, containing up to 2.5% water, is seeded with Polymorph, then cooled to a temperature in the range of 20°C to 25°C; polymorph then regenerates from solvent. 10. A pharmaceutical composition containing an effective, non-toxic amount of the Polymorph according to claim 1 and its pharmaceutically acceptable carrier. 11. Polymorph according to claim 1, for use as an active therapeutic substance. 12. Polymorph according to claim 1, for use in the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and some of their complications. 13. Use of Polymorph according to claim 1, for obtaining a drug for the treatment and/or prophylaxis of diabetes mellitus, conditions associated with diabetes mellitus and some of their complications.